Our overall goal to understand the role of the adipokine adiponectin in vascular function, atherosclerosis,[unreadable] and coronary heart disease. Adiponectin is produced exclusively by adipocytes and is found at high levels[unreadable] in the intima surrounding several types of blood vessels. Adiponectin plays a key role in regulating[unreadable] hepatic and muscle fat and glucose metabolism and also the metabolism and proliferation of vascular[unreadable] smooth muscle and possibly endothelial cells. We identified several adiponectin orthologs, expressed[unreadable] mainly by adipocytes that share biological activities and signaling properties with adiponectin; these, like[unreadable] adiponectin, may regulate metabolism of vascular cells. The identities of the adiponectin signaling[unreadable] receptors and signal transduction pathways are not known; our and other labs have unequivocally shown[unreadable] that previously reported, putative signaling receptors for adiponectin do not function in that capacity. We[unreadable] identified T-cadherin, a GPI- anchored surface protein, as an adiponectin binding protein that is highly and[unreadable] specifically expressed by cells in the blood vessel intima. Deletion of T-cadherin in mice results in a[unreadable] decrease in adiponectin in the vasculature and a major increase in the circulation, indicating it is a major[unreadable] adiponectin receptor. However, additional cell surface receptors are necessary to mediate adiponectin[unreadable] signaling. We will clone these signaling adiponectin receptors, analyze their structures and functions in[unreadable] vitro and in vivo, and determine the signal transduction pathways activated in cultured vascular endothelial[unreadable] and smooth muscle cells by the three isoforms of adiponectin, focusing initially on the AMP- activated[unreadable] protein kinase, and NF-kB, MAP kinase, and NO pathways. Cells from T-cadherin -/- mice will allow us to[unreadable] continue to explore the role of this receptor in adiponectin signaling and localization in the vasculature.[unreadable] Importantly, with Projects I and II we will determine the effects of the various isoforms and orthologs of[unreadable] adiponectin and of T-cadherin on blood vessel endothelial and smooth muscle cells and on[unreadable] atherosclerosis and CHD in apoE -/- and SR-BI/apoE double knockout (dKO) mice. Thus, over the[unreadable] coming five years we hope to elucidate the roles of adiponectin and its principal vascular binding protein,[unreadable] T-cadherin, in maintaining the normal state of vascular endothelial and smooth muscle cells, and[unreadable] understand whether and how deletion of either of these proteins leads to atherosclerosis, thrombosis and[unreadable] CHD.